Maintaining a healthy body weight has both medical and cosmetic benefits and there is a large industry devoted to gaining or losing weight. Eating disorders are recognised as an increasing epidemic, with both excessive and insufficient food intake increasing in occurrence. Common eating disorders are overeating (leading to obesity), anorexia nervosa and bulimia. Cachexia, i.e. the unintentional loss of weight, is also a major problem in certain diseases.
Nearly two thirds of the adult population of the USA is overweight or obese, based on a body mass index (BMI, i.e. body weight in kilogram divided by the squared height in m) above 25 or 30, respectively. The obese subgroup has increased from 13.3% in 1964 to more than double that value with 32.9% in 2004 (Ogden et al, Gastroenterology 132, 2087-102 (2007) and Bray, G. A. & Bellanger, T. Endocrine 29, 109-17 (2006)).
Anorexia nervosa is characterised by low body weight and body image distortion, with an excessive fear of gaining weight. It has a prevalence of 0.3% to 1.3% in the Western population; this incidence is thought to be rising (Bulik et al, Int J Eat Disord 2005; 37:S2-S9).
Bulimia (also known as bulimia nervosa) is characterized by binge-eating followed by intentional purging, such as vomiting. It has a prevalence of approximately 1% in the Western adult population, although prevalence is significantly higher in young women (Bushnell et al, Psychol Med. 1990 August; 20(3): 671-680).
Cachexia involves muscle atrophy, a loss of weight and a loss of appetite in a subject that is not actively trying to lose weight. Cachexia is often seen in late-stage cancer and AIDS patients.
The exact mechanisms involved in gaining, losing or maintaining body weight are not understood. It is known that eating disorders and cachexia are governed by a combination of psychological and physiological factors. It is known that gastrointestinal hormones are involved in the regulation of appetite.
In particular, the hormone leptin is known to be a fat-derived anorexigenic hormone that signals the fuel storage level to the brain (Zhang, Y. et al. Nature 372, 425-32 (1994)). In short, leptin reduces appetite. Several other gastrointestinal anorexigenic hormones have been identified (Drucker, D. J. J Clin Invest 117, 24-32 (2007)).
Conversely, the gastrointestinal hormone ghrelin is the only known orexigenic hormone, i.e. the only hormone that is known to increase appetite (Asakawa, A. et al. Gut 52, 947-52 (2003)). In contrast to anorexigenic hormones which are secreted in response to food intake, ghrelin surges before meal initiation and is suppressed by food intake. Administration of ghrelin stimulates food intake in a wide variety of species.
The identification of receptors for hormones that affect appetite and food intake has been the subject of considerable scientific research in recent years. Recently, the G-protein coupled receptor GPR100 (also referred to as GPCR 142, relaxin-3 receptor-2 and RXFP4) was identified as involved in the regulation of obesity (WO-A-2005/124361). The peptide hormone Insl5 has recently been identified as the endogenous ligand of GPR100 (Liu at al J. Biol. Chem., Vol. 280, Issue 1, 292-300, Jan. 7, 2005).
Although a number of hormones, such as leptin and ghrelin, have been identified as potential therapeutics to regulate body weight, clinical results to date (for leptin at least) have been disappointing. Therefore, there remains a strong need to identify further agents that can regulate appetite and food intake.